Article

Cardiac Toxicity of Cancer Chemotherapy

Register or Login to View PDF Permissions
Permissions× For commercial reprint enquiries please contact Springer Healthcare: ReprintsWarehouse@springernature.com.

For permissions and non-commercial reprint enquiries, please visit Copyright.com to start a request.

For author reprints, please email rob.barclay@radcliffe-group.com.
Average (ratings)
No ratings
Your rating

Abstract

With the aging of the population, the number of patients diagnosed with cancer has grown significantly over the past few decades. In parallel, survival rates have improved due to the increased efficacy and tolerability of cancer treatments. As such, the acute and long-term toxicities of cancer therapies have become increasingly prominent as contributors to morbidity and mortality in cancer survivors. Cardiac toxicity can occur with a broad range of cancer treatments, from conventional cytotoxic agents to newer targeted and immune-based therapies. Common manifestations of chemotherapy-associated cardiotoxicity include asymptomatic left ventricular dysfunction, congestive heart failure, myocardial ischemia, myocarditis, QT prolongation, and arrhythmia. In this review, we will describe antitumor agents that have commonly been associated with an increased risk of cardiac toxicity, with an emphasis on clinical manifestations, underlying mechanisms, and cardioprotective strategies that can be implemented in this setting.

Disclosure:The authors have no conflicts of interest to declare.

Received:

Accepted:

Correspondence Details:Aarti Asnani, MD, Cardio-Oncology Program and Cardiovascular Research Center, Massachusetts General Hospital, 149 13th Street, Room 4.302, Boston, MA 02129, USA. E: aasnani@mgh.harvard.edu

Copyright Statement:

The copyright in this work belongs to Radcliffe Medical Media. Only articles clearly marked with the CC BY-NC logo are published with the Creative Commons by Attribution Licence. The CC BY-NC option was not available for Radcliffe journals before 1 January 2019. Articles marked ‘Open Access’ but not marked ‘CC BY-NC’ are made freely accessible at the time of publication but are subject to standard copyright law regarding reproduction and distribution. Permission is required for reuse of this content.

Survival rates among patients diagnosed with cancer have improved dramatically over the past few decades. In 2016, there were an estimated 16 million cancer survivors in the United States, a number expected to increase to 20 million over the subsequent decade.1 One-third of these patients will survive at least 5 years after their initial cancer diagnosis, largely due to cancer therapies that are more efficacious and better tolerated. However, many of these treatments have the potential to contribute to cardiac toxicities that can affect quality of life, and in many cases, overall survival (see Table 1). Moreover, the development of cardiac toxicities can prevent clinicians from achieving effective doses of chemotherapy or prompt them to choose suboptimal cancer treatment regimens. At present, data to guide management of chemotherapyinduced cardiac toxicities stem from observational studies and small randomized trials, and the majority of recommendations are driven by clinical expertise (see Table 2). Here we will review a number of antitumor agents that have been associated with significant cardiac toxicity, from traditional cytotoxic chemotherapies that have been in use for decades to the newer targeted therapies and immune checkpoint inhibitors.

Cytotoxic Chemotherapy

Anthracyclines

The anthracyclines were the first major class of chemotherapies to be associated with cardiac toxicity. Anthracyclines are derivatives of Streptomyces that were originally discovered to have antitumor properties in the 1960s2 and first linked to cardiac toxicity in the early 1970s.3 Given the extensive data supporting their efficacy, anthracyclines are commonly used for the treatment of breast cancer, leukemia, lymphoma, and sarcoma, despite the advent of newer targeted therapies. The anthracycline doxorubicin (Adriamycin®) is well recognized for increasing the risk of cardiomyopathy, with the risk of congestive heart failure (CHF) increasing in proportion to the lifetime cumulative dose administered.4 Although the highest rates of cardiac toxicity have been described with cumulative doses exceeding 400 mg/m2, CHF has been reported in patients exposed to much lower doses.5 A recent study suggested that 9 % of patients treated with anthracyclines experienced cardiotoxicity, defined as a decline in left ventricular ejection fraction by >10 percentage points to an absolute value of <50 % within the first year following completion of anthracycline-based chemotherapy.6 Importantly, the risk of anthracycline-associated cardiotoxicity increases substantially when combined with other common cancer treatments such as chest radiation and trastuzumab.7

Despite decades of investigation, the precise mechanisms of anthracycline-induced cardiotoxicity have not been well defined. Prior work has focused primarily on the role of oxidative stress.8 Doxorubicin forms a semiquinone radical that reacts rapidly with oxygen to form a superoxide anion, leading to the production of hydroxyl radicals in the presence of heavy metals such as iron.9 In addition, doxorubicin binds directly to iron to generate free radicals.10 Doxorubicin-induced oxidative stress has been proposed to be mediated by mitochondrial iron accumulation,11 doxorubicin’s interaction with the beta isoform of topoisomerase II (Top2beta),12 and autophagy.13 However, despite evidence implicating oxidative stress as a common downstream feature of doxorubicin-induced cardiomyopathy, antioxidants are ineffective in preventing cardiotoxicity in patients.14,15 Similarly, iron chelators such as deferasirox have failed to protect against doxorubicin cardiotoxicity in preclinical models.16 Liposomal formulations can be used as alternatives to traditional anthracyclines with reduced rates of cardiotoxicity.17 These agents preferentially enter into the leaky microvasculature of tumors, but have limited extravasation into cardiomyocytes.18 Given the increased cost of liposomal formulations, as well as the increased risk of mucositis and hand–foot syndrome, they are used primarily in the setting of refractory or metastatic disease where high doses of anthracyclines are required.

Table 1: Mechanisms of Cardiotoxicity Associated with Cancer Treatments

Article image

Based on extensive literature supporting the use of neurohormonal blockade in other types of cardiomyopathy, a few small, randomized clinical trials have been performed to examine the role of beta blockade and angiotensin-receptor blockade for the primary prevention of anthracycline-induced LV dysfunction.19–23 Currently, dexrazoxane is the only U.S. Food and Drug Administration (FDA)-approved drug used clinically to prevent doxorubicin-induced cardiomyopathy. It is believed to chelate intracellular iron, block iron-assisted oxidative radical production, and inhibit Top2beta.11,12,24,25 In practice, however, the use of dexrazoxane has been limited by concerns that it may interfere with doxorubicin’s ability to kill tumor cells26 and may also induce secondary malignancies.27 As such, the FDA has restricted its use to patients with metastatic breast cancer who have received a cumulative lifetime dose of at least 300 mg/m2 of doxorubicin or an equivalent dose of other anthracyclines. However, subsequent trials have not suggested any decrease in antitumor efficacy with the use of dexrazoxane, and similar oncologic response rates were reported in a large Cochrane meta-analysis.28 Similarly, two subsequent reports of childhood survivors of acute lymphoblastic leukemia who were treated with dexrazoxane did not suggest any increase in the rate of secondary malignancies.29,30 Thus, many clinicians continue to prescribe dexrazoxane in patients receiving a high cumulative dose of anthracyclines, particularly in those with pre-existing cardiovascular disease or other risk factors for the development of cardiotoxicity.

Table 2: Clinical Manifestations and Management of Cardiotoxicity Associated with Cancer Treatments

Article image

Fluoropyrimidines

The fluoropyrimidines 5-fluorouracil and its oral prodrug capecitabine are commonly used in the treatment of gastrointestinal malignancies. Coronary vasospasm leading to myocardial ischemia has been widely described in association with fluoropyrimidine treatment, typically manifested by the development of angina.31 Notably, the presence of pre-existing ischemic heart disease may increase the risk of developing fluoropyrimidine-induced cardiotoxicity.32 CHF, myocarditis, and ventricular arrhythmias have also been reported, suggesting a direct myocardial toxicity.33–35 Although cardiotoxicity is typically reversible on withdrawal of the offending agent, sudden death has been reported in the setting of fluoropyrimidine use.36 Proposed mechanisms of coronary vasospasm include protein kinase C-mediated vasoconstriction,37 impaired handling of reactive oxygen species,38 and direct endothelial toxicity.39 Calcium-channel blockers and nitrates are often prescribed for prophylaxis in patients suspected to have fluoropyrimidine-induced coronary vasospasm, although their efficacy in preventing subsequent episodes of vasospasm is debated.

Targeted Therapies

Anti-Human Epidermal Growth Factor Receptor 2 Therapy

Recent developments in molecular profiling have led to a rapid increase in the number of cancer therapies targeting specific tyrosine kinases that are overexpressed in tumor tissue, particularly those involved in growth factor signaling. At present, the most commonly used targeted therapies are those that inhibit the human epidermal growth factor receptor 2 (HER2), which is overexpressed in approximately 25 % of all breast tumors,40 as well as some gastrointestinal and other tumors. Currently available therapies targeting the HER2 receptor include two humanized monoclonal antibodies, trastuzumab and pertuzumab, as well as the small-molecule inhibitor lapatinib. Cardiotoxicity arising from these therapies is most likely an on-target effect, as signaling through the HER2/neuregulin pathway is important in the cardiomyocyte response to injury during myocardial ischemia41 and anthracycline exposure.42

Initial studies demonstrated rates of LV dysfunction as high as 8 % for trastuzumab alone and 30 % for concomitant trastuzumab and anthracycline therapy,43 although estimates of cardiac toxicity have varied widely in subsequent clinical trials and community-based observational studies. Recent data suggest that combination therapy incorporating both trastuzumab and pertuzumab does not seem to increase the risk of cardiotoxicity.44 Of the three agents currently in use, lapatinib appears to be associated with the lowest risk of cardiotoxicity.45 Interruption or cessation of anti-HER2 therapy often results in recovery of LV function, although breast cancer outcomes may be affected as a result.46 If trastuzumab is interrupted due to cardiotoxicity, many patients experience recovery of LV function and can be safely re-challenged to complete a course of therapy. Late cardiotoxicity does not seem to occur after cessation of anti-HER2 therapy, unless patients are re-exposed to cardiotoxic chemotherapy.47

Vascular Endothelial Growth Factor Pathway Inhibitors

Inhibitors of the vascular endothelial growth factor signaling pathway are becoming increasingly used in the treatment of a number of malignancies, in particular renal cell carcinoma and gastrointestinal stromal tumor. Currently available agents range from monoclonal antibodies such as bevacizumab to small-molecule inhibitors such as sunitinib and sorafenib. Most of the small-molecule inhibitors in use today are multitargeted and thus affect the activity of a number of different tyrosine kinases, making it difficult to ascertain whether cardiotoxicity is related to on-target and/or off-target effects. In general, agents with a broad kinome-binding profile such as sunitinib have been associated with high rates of hypertension and LV dysfunction, although these effects are often reversible on discontinuation of the offending agent.48 It remains unclear whether the cardiomyopathy observed with these agents stems from direct toxicity to cardiomyocytes, or whether it is secondary to underlying vascular dysfunction and endothelial toxicity.49 Hypertension does appear to be an on-target effect, and in renal cell carcinoma, the development of hypertension correlates with increased efficacy of treatment and improved cancer outcomes.50 QT prolongation has also been observed with many of these agents51 and may be exacerbated by electrolyte abnormalities and other QT-prolonging medications such as antiemetics. In general, a prolongation of the corrected QT interval to >500 ms warrants a discussion of the risks and benefits of continuing therapy, although the underlying mechanisms and risk of developing torsades de pointes in this setting remain unclear.

Ibrutinib

The irreversible Bruton’s tyrosine kinase (BTK) inhibitor ibrutinib has been associated with high rates of AF. Ibrutinib is currently used for the treatment of relapsed or refractory chronic lymphocytic leukemia and mantle cell lymphoma as well as Waldenström macroglobulinemia. Initial clinical trials demonstrated rates of AF ranging 3–12 % in patients treated with ibrutinib.52,53 Notably, patients in these studies were older and had prior exposure to anthracyclines, factors that may have contributed to the high rates of AF observed. Preliminary work suggests that on-target effects may contribute to ibrutinib-mediated AF.54 However, newer BTK inhibitors have not been associated with increased rates of AF,55 suggesting an off-target mechanism. Although discontinuation of ibrutinib therapy is necessary in some patients, others respond well to standard treatments for AF and can continue ibrutinib at a full or reduced dose.56

Immune Checkpoint Inhibitors

The use of immune checkpoint blockade has become widespread for the treatment of metastatic melanoma57–59 and increasingly for other indications such as non-small cell lung cancer60 and renal cell carcinoma.61 Currently available agents include pembrolizumab, nivolumab, and atezolizumab, which target the programmed cell death protein-1 (PD-1) pathway, and ipilimumab, which targets cytotoxic T-lymphocyteassociated protein 4 (CTLA-4). These monoclonal antibodies modulate the T-cell-inhibitory responses that allow for tumor evasion from host immunity. As a result, treatment with these agents results in T-cell activation and proliferation, prompting a robust immune response against cancer cells.62

The cardiotoxicity of immune checkpoint inhibitors, while rare, has become increasingly important with the application of these therapies to expanding populations, especially when anti-PD-1 and anti-CTLA-4 agents are used in combination. Myocarditis is the predominant manifestation of cardiotoxicity, as described in initial clinical trials63,64 as well as case reports.65 A recent report highlighted two patients treated with combination immune checkpoint blockade and diagnosed with myositis as well as fulminant myocarditis; both patients died from cardiotoxicity.66 In these patients, endomyocardial biopsy demonstrated clonal T-cell infiltrates that were similar to those seen in tumor tissue. Preclinical models have suggested that modulation of the PD-1 pathway can lead to immune-mediated cardiovascular toxicity, primarily in the form of autoimmune myocarditis. Knockout of the PD-1 receptor in mice causes severe dilated cardiomyopathy characterized by high levels of immunoglobulin G autoantibodies that react specifically to cardiac troponin I.67,68 In mouse models of lupus and other experimentally induced inflammatory states, the PD-1 pathway has been recognized as an essential mediator of autoimmune myocarditis69–71 and has been similarly associated with high-titer autoantibodies against cardiac myosin.71 Proposed therapies include high-dose steroids, anti-tumor necrosis factor-alpha antibodies such as infliximab, and antithymocyte globulin, although there is currently no evidence to support an improvement in clinical outcomes with these measures.

Conclusion

Over the past decade, efficient, target-based development of antitumor agents has facilitated the introduction of several new cancer therapies, many of which are being approved for new types of malignancy each year. In 2016 alone, the FDA approved the use of targeted therapies and immune checkpoint inhibitors for 19 new indications.72 Many targeted cancer therapies are relatively well tolerated compared with conventional cytotoxic chemotherapy, enabling long-term use in some patients. Cardiologists will thus be faced with the challenge of managing a range of cardiac toxicities that can significantly impact patient morbidity and mortality. Efforts to understand the underlying mechanisms and molecular predictors of cardiotoxicity will be essential to identify patients at high risk and to guide decisions regarding cardioprotection. Collaboration between cardiologists and oncologists in managing cardiotoxicity will be of the utmost importance to ensure the best outcomes in patients receiving these therapies.

References

  1. Bluethmann SM, Mariotto AB, Rowland JH. Anticipating the “Silver Tsunami”: prevalence trajectories and comorbidity burden among older cancer survivors in the United States. Cancer Epidemiol Biomarkers Prev 2016;25:1029–36.
    Crossref | PubMed
  2. Dubost M, Ganter P, Maral R, et al. A New antibiotic with cytostatic properties: rubidomycin. C R Hebd Seances Acad Sci 1963;257:1813–5.
    PubMed
  3. Lefrak EA, Pitha J, Rosenheim S, Gottlieb JA. A clinicopathologic analysis of adriamycin cardiotoxicity. Cancer 1973;32:302–14.
    Crossref | PubMed
  4. Mulrooney DA, Yeazel MW, Kawashima T, et al. Cardiac outcomes in a cohort of adult survivors of childhood and adolescent cancer: retrospective analysis of the Childhood Cancer Survivor Study cohort. BMJ 2009;339:b4606.
    Crossref | PubMed
  5. Von Hoff DD, Layard MW, Basa P, et al. Risk factors for doxorubicin-induced congestive heart failure. Ann Intern Med 1979;91:710–7.
    Crossref | PubMed
  6. Cardinale D, Colombo A, Bacchiani G, et al. Early detection of anthracycline cardiotoxicity and improvement with heart failure therapy. Circulation 2015;131:1981–8.
    Crossref | PubMed
  7. Bowles EJ, Wellman R, Feigelson HS, et al. Risk of heart failure in breast cancer patients after anthracycline and trastuzumab treatment: a retrospective cohort study. J Natl Cancer Inst 2012;104:1293–305.
    Crossref | PubMed
  8. Octavia Y, Tocchetti CG, Gabrielson KL, et al. Doxorubicininduced cardiomyopathy: from molecular mechanisms to therapeutic strategies. J Mol Cell Cardiol 2012;52:1213–25.
    Crossref | PubMed
  9. Myers C. The role of iron in doxorubicin-induced cardiomyopathy. Semin Oncol 1998;25(4 Suppl 10):10–4.
    PubMed
  10. Xu X, Persson HL, Richardson DR. Molecular pharmacology of the interaction of anthracyclines with iron. Mol Pharmacol 2005;68:261–71.
    Crossref | PubMed
  11. Ichikawa Y, Ghanefar M, Bayeva M, et al. Cardiotoxicity of doxorubicin is mediated through mitochondrial iron accumulation. J Clin Invest 2014;124:617–30.
    Crossref | PubMed
  12. Zhang S, Liu X, Bawa-Khalfe T, et al. Identification of the molecular basis of doxorubicin-induced cardiotoxicity. Nat Med 2012;18:1639–42.
    Crossref | PubMed
  13. Li DL, Wang ZV, Ding G, et al. Doxorubicin blocks cardiomyocyte autophagic flux by inhibiting lysosome acidification. Circulation 2016;133:1668–87.
    Crossref | PubMed
  14. Myers C, Bonow R, Palmeri S, et al. A randomized controlled trial assessing the prevention of doxorubicin cardiomyopathy by N-acetylcysteine. Semin Oncol 1983;10(1 Suppl 1):53–5.
    PubMed
  15. Legha SS, Wang YM, Mackay B, et al. Clinical and pharmacologic investigation of the effects of alpha-tocopherol on adriamycin cardiotoxicity. Ann N Y Acad Sci 1982;393:411–8.
    Crossref | PubMed
  16. Hasinoff BB, Patel D, Wu X. The oral iron chelator ICL670A (deferasirox) does not protect myocytes against doxorubicin. Free Radic Biol Med 2003;35:1469–79. PMID: .
    Crossref | PubMed
  17. van Dalen EC, Michiels EM, Caron HN, Kremer LC. Different anthracycline derivates for reducing cardiotoxicity in cancer patients. Cochrane Database Syst Rev 2010(5):CD005006.
    Crossref | PubMed
  18. Drummond DC, Meyer O, Hong K, et al. Optimizing liposomes for delivery of chemotherapeutic agents to solid tumors. Pharmacol Rev 1999;51:691–743.
    PubMed
  19. Kalay N, Basar E, Ozdogru I, et al. Protective effects of carvedilol against anthracycline-induced cardiomyopathy. J Am Coll Cardiol 2006;48:2258–62.
    Crossref | PubMed
  20. Kaya MG, Ozkan M, Gunebakmaz O, et al. Protective effects of nebivolol against anthracycline-induced cardiomyopathy: a randomized control study. Int J Cardiol 2013;167:2306–10.
    Crossref | PubMed
  21. Georgakopoulos P, Roussou P, Matsakas E, et al. Cardioprotective effect of metoprolol and enalapril in doxorubicin-treated lymphoma patients: a prospective, parallel-group, randomized, controlled study with 36-month follow-up. Am J Hematol 2010;85:894–6.
    Crossref | PubMed
  22. Gulati G, Heck SL, Ree AH, et al. Prevention of cardiac dysfunction during adjuvant breast cancer therapy (PRADA): a 2 x 2 factorial, randomized, placebo-controlled, doubleblind clinical trial of candesartan and metoprolol. Eur Heart J 2016;37:1671–80.
    Crossref | PubMed
  23. Bosch X, Rovira M, Sitges M, et al. Enalapril and carvedilol for preventing chemotherapy-induced left ventricular systolic dysfunction in patients with malignant hemopathies: the OVERCOME trial (preventiOn of left Ventricular dysfunction with Enalapril and caRvedilol in patients submitted to intensive ChemOtherapy for the treatment of Malignant hEmopathies). J Am Coll Cardiol 2013;61:2355–62.
    Crossref | PubMed
  24. Hasinoff BB, Herman EH. Dexrazoxane: how it works in cardiac and tumor cells. Is it a prodrug or is it a drug? Cardiovasc Toxicol 2007;7:140–4.
    Crossref | PubMed
  25. Lyu YL, Kerrigan JE, Lin CP, et al. Topoisomerase IIbeta mediated DNA double-strand breaks: implications in doxorubicin cardiotoxicity and prevention by dexrazoxane. Cancer Res 2007;67:8839–46.
    Crossref | PubMed
  26. Swain SM, Whaley FS, Gerber MC, et al. Cardioprotection with dexrazoxane for doxorubicin-containing therapy in advanced breast cancer. J Clin Oncol 1997;15:1318–32.
    Crossref | PubMed
  27. Tebbi CK, London WB, Friedman D, et al. Dexrazoxaneassociated risk for acute myeloid leukemia/myelodysplastic syndrome and other secondary malignancies in pediatric Hodgkin’s disease. J Clin Oncol 2007;25(5):493–500.
    Crossref | PubMed
  28. van Dalen EC, Caron HN, Dickinson HO, Kremer LC. Cardioprotective interventions for cancer patients receiving anthracyclines. Cochrane Database Syst Rev 2011(6):CD003917.
    Crossref | PubMed
  29. Salzer WL, Devidas M, Carroll WL, et al. Long-term results of the pediatric oncology group studies for childhood acute lymphoblastic leukemia 1984-2001: a report from the children’s oncology group. Leukemia 2010;24:355–70.
    Crossref | PubMed
  30. Vrooman LM, Neuberg DS, Stevenson KE, et al. The low incidence of secondary acute myelogenous leukaemia in children and adolescents treated with dexrazoxane for acute lymphoblastic leukaemia: a report from the Dana-Farber Cancer Institute ALL Consortium. Eur J Cancer 2011;47:1373–9.
    Crossref | PubMed
  31. Layoun ME, Wickramasinghe CD, Peralta MV, Yang EH. Fluoropyrimidine-induced cardiotoxicity: manifestations, mechanisms, and management. Curr Oncol Report 2016;18:35.
    Crossref | PubMed
  32. Meyer CC, Calis KA, Burke LB, et al. Symptomatic cardiotoxicity associated with 5-fluorouracil. Pharmacotherapy 1997;17:729–36.
    PubMed
  33. Fradley MG, Barrett CD, Clark JR, Francis SA. Ventricular fibrillation cardiac arrest due to 5-fluorouracil cardiotoxicity. Tex Heart Inst J 2013;40:472–6.
    PubMed
  34. Rateesh S, Shekar K, Naidoo R, et al. Use of extracorporeal membrane oxygenation for mechanical circulatory support in a patient with 5-fluorouracil induced acute heart failure. Circ Heart Fail 2015;8:381–3.
    Crossref | PubMed
  35. Amraotkar AR, Pachika A, Grubb KJ, DeFilippis AP. Rapid extracorporeal membrane oxygenation overcomes fulminant myocarditis induced by 5-Fluorouracil. Tex Heart Inst J 2016;43:178–82.
    Crossref | PubMed
  36. Hannaford R. Sudden death associated with 5-fluorouracil. Med J Aust 1994;161:225.
    PubMed
  37. Mosseri M, Fingert HJ, Varticovski L, et al. In vitro evidence that myocardial ischemia resulting from 5-fluorouracil chemotherapy is due to protein kinase C-mediated vasoconstriction of vascular smooth muscle. Cancer Res 1993;53:3028–33.
    PubMed
  38. Durak I, Karaayvaz M, Kavutcu M, et al. Reduced antioxidant defense capacity in myocardial tissue from guinea pigs treated with 5-fluorouracil. J Toxicol Environ Health 2000;59:585–9.
    Crossref | PubMed
  39. Tsibiribi P, Bui-Xuan C, Bui-Xuan B, et al. Cardiac lesions induced by 5-fluorouracil in the rabbit. Hum Exp Toxicol 2006;25:305–9.
    Crossref | PubMed
  40. Bilous M, Ades C, Armes J, et al. Predicting the HER2 status of breast cancer from basic histopathology data: an analysis of 1500 breast cancers as part of the HER2000 International Study. Breast 2003;12:92–8.
    Crossref | PubMed
  41. D’Uva G, Aharonov A, Lauriola M, et al. ERBB2 triggers mammalian heart regeneration by promoting cardiomyocyte dedifferentiation and proliferation. Nat Cell Biol 2015;17:627–38.
    Crossref | PubMed
  42. Timolati F, Ott D, Pentassuglia L, et al. Neuregulin-1 beta attenuates doxorubicin-induced alterations of excitationcontraction coupling and reduces oxidative stress in adult rat cardiomyocytes. J Mol Cell Cardiol 2006;41:845–54.
    Crossref | PubMed
  43. Seidman A, Hudis C, Pierri MK, et al. Cardiac dysfunction in the trastuzumab clinical trials experience. J Clin Oncol 2002;20: 1215–21.
    Crossref | PubMed
  44. Swain SM, Baselga J, Kim SB, et al. Pertuzumab, trastuzumab, and docetaxel in HER2-positive metastatic breast cancer. N Engl J Med 2015;372:724–34.
    Crossref | PubMed
  45. Perez EA, Koehler M, Byrne J, et al. Cardiac safety of lapatinib: pooled analysis of 3689 patients enrolled in clinical trials. Mayo Clin Proc 2008;83:679–86.
    Crossref | PubMed
  46. Witzel I, Muller V, Abenhardt W, et al. Long-term tumor remission under trastuzumab treatment for HER2 positive metastatic breast cancer - results from the HER-OS patient registry. BMC Cancer 2014;14:806.
    Crossref | PubMed
  47. Mayer EL, Gropper AB, Harris L, et al. Long-term follow-up after preoperative trastuzumab and chemotherapy for HER2- overexpressing breast cancer. Clin Breast Cancer 2015;15:24–30.
    Crossref | PubMed
  48. Ewer MS, Suter TM, Lenihan DJ, et al. Cardiovascular events among 1090 cancer patients treated with sunitinib, interferon, or placebo: a comprehensive adjudicated database analysis demonstrating clinically meaningful reversibility of cardiac events. Eur J Cancer 2014;50:2162–70.
    Crossref | PubMed
  49. Force T, Krause DS, Van Etten RA. Molecular mechanisms of cardiotoxicity of tyrosine kinase inhibition. Nat Rev Cancer 2007;7:332–44.
    Crossref | PubMed
  50. Rautiola J, Donskov F, Peltola K, et al. Sunitinib-induced hypertension, neutropaenia and thrombocytopaenia as predictors of good prognosis in patients with metastatic renal cell carcinoma. BJU Int 2016;117:110–7.
    Crossref | PubMed
  51. Kloth JS, Pagani A, Verboom MC, et al. Incidence and relevance of QTc-interval prolongation caused by tyrosine kinase inhibitors. Br J Cancer 2015;112:1011–6.
    Crossref | PubMed
  52. Byrd JC, Brown JR, O’Brien S, et al. Ibrutinib versus ofatumumab in previously treated chronic lymphoid leukemia. N Engl J Med 2014;371:213–23.
    Crossref | PubMed
  53. Wang ML, Lee H, Chuang H, et al. Ibrutinib in combination with rituximab in relapsed or refractory mantle cell lymphoma: a single-centre, open-label, phase 2 trial. Lancet Oncol 2016;17: 48–56.
    Crossref | PubMed
  54. McMullen JR, Boey EJ, Ooi JY, et al. Ibrutinib increases the risk of atrial fibrillation, potentially through inhibition of cardiac PI3K-Akt signaling. Blood 2014;124:3829–30.
    Crossref | PubMed
  55. Byrd JC, Harrington B, O’Brien S, et al. Acalabrutinib (ACP-196) in relapsed chronic lymphocytic leukemia. N Engl J Med 2016;374: 323–32.
    Crossref | PubMed
  56. Thompson PA, Levy V, Tam CS, et al. Atrial fibrillation in CLL patients treated with ibrutinib. An international retrospective study. Br J Haematol 2016;175:462–6.
    Crossref | PubMed
  57. Robert C, Thomas L, Bondarenko I, et al. Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N Engl J Med 2011;364:2517–26.
    Crossref | PubMed
  58. Weber JS, D’Angelo SP, Minor D, et al. Nivolumab versus chemotherapy in patients with advanced melanoma who progressed after anti-CTLA-4 treatment (CheckMate 037): a randomised, controlled, open-label, phase 3 trial. Lancet Oncol 2015;16:375–84.
    Crossref | PubMed
  59. Larkin J, Chiarion-Sileni V, Gonzalez R, et al. Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N Engl J Med 2015;373:23–34.
    Crossref | PubMed
  60. Borghaei H, Paz-Ares L, Horn L, et al. Nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer. N Engl J Med 2015;373:1627–39.
    Crossref | PubMed
  61. Motzer RJ, Escudier B, McDermott DF, et al. Nivolumab versus everolimus in advanced renal-cell carcinoma. N Engl J Med 2015;373:1803–13.
    Crossref | PubMed
  62. Sharma P, Allison JP. Immune checkpoint targeting in cancer therapy: toward combination strategies with curative potential. Cell 2015;161:205–14.
    Crossref | PubMed
  63. Eggermont AM, Chiarion-Sileni V, Grob JJ, et al. Adjuvant ipilimumab versus placebo after complete resection of high-risk stage III melanoma (EORTC 18071): a randomised, double-blind, phase 3 trial. Lancet Oncol 2015;16:522–30.
    Crossref | PubMed
  64. Brahmer JR, Tykodi SS, Chow LQ, et al. Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N Engl J Med 2012;366:2455–65.
    Crossref | PubMed
  65. Laubli H, Balmelli C, Bossard M, et al. Acute heart failure due to autoimmune myocarditis under pembrolizumab treatment for metastatic melanoma. J Immunother Cancer 2015;3:11.
    Crossref | PubMed
  66. Johnson DB, Balko JM, Compton ML, et al. Fulminant myocarditis with combination immune checkpoint blockade. N Engl J Med 2016;375:1749–55.
    Crossref | PubMed
  67. Nishimura H, Okazaki T, Tanaka Y, et al. Autoimmune dilated cardiomyopathy in PD-1 receptor-deficient mice. Science 2001;291:319–22.
    Crossref | PubMed
  68. Okazaki T, Tanaka Y, Nishio R, et al. Autoantibodies against cardiac troponin I are responsible for dilated cardiomyopathy in PD-1-deficient mice. Nat Med 2003;9:1477–83.
    Crossref | PubMed
  69. Lucas JA, Menke J, Rabacal WA, et al. Programmed death ligand 1 regulates a critical checkpoint for autoimmune myocarditis and pneumonitis in MRL mice. J Immunol 2008;181:2513–21.
    Crossref | PubMed
  70. Tarrio ML, Grabie N, Bu DX, et al. PD-1 protects against inflammation and myocyte damage in T cell-mediated myocarditis. J Immunol 2012;188:4876–84.
    Crossref | PubMed
  71. Wang J, Okazaki IM, Yoshida T, et al. PD-1 deficiency results in the development of fatal myocarditis in MRL mice. Int Immunol 2010;22:443–52.
    Crossref | PubMed
  72. U.S. Food and Drug Administration. Hematology/Oncology (Cancer) Approvals & Safety Notifications. Available at: http://bit.ly/2lQn47e (accessed February 23, 2017)
  73. Doroshow JH, Davies KJ. Redox cycling of anthracyclines by cardiac mitochondria. II. Formation of superoxide anion, hydrogen peroxide, and hydroxyl radical. J Biol Chem 1986;261:3068–74.
    PubMed
  74. Rajagopalan S, Politi PM, Sinha BK, Myers CE. Adriamycin-induced free radical formation in the perfused rat heart: implications for cardiotoxicity. Cancer Res 1988;48:4766–9.
    PubMed
  75. Zhou S, Starkov A, Froberg MK, et al. Cumulative and irreversible cardiac mitochondrial dysfunction induced by doxorubicin. Cancer Res 2001;61:771–7.
    PubMed
  76. Liu Y, Asnani A, Zou L, et al. Visnagin protects against doxorubicininduced cardiomyopathy through modulation of mitochondrial malate dehydrogenase. Sci Transl Med 2014;6:266ra170.
    Crossref | PubMed
  77. Chintalgattu V, Rees ML, Culver JC, et al. Coronary microvascular pericytes are the cellular target of sunitinib malate-induced cardiotoxicity. Sci Transl Med 2013;5:187ra69.
    Crossref | PubMed
  78. Cheng H, Kari G, Dicker AP, et al. A novel preclinical strategy for identifying cardiotoxic kinase inhibitors and mechanisms of cardiotoxicity. Circ Res 2011;109:1401–9.
    Crossref | PubMed
  79. Cardinale D, Colombo A, Sandri MT, et al. Prevention of high-dose chemotherapy-induced cardiotoxicity in high-risk patients by angiotensin-converting enzyme inhibition. Circulation 2006;114:2474–81.
    Crossref | PubMed
  80. Cardinale D, Colombo A, Lamantia G, et al. Anthracyclineinduced cardiomyopathy: clinical relevance and response to pharmacologic therapy. J Am Coll Cardiol 2010;55:213–20.
    Crossref | PubMed
  81. Acar Z, Kale A, Turgut M, et al. Efficiency of atorvastatin in the protection of anthracycline-induced cardiomyopathy. J Am Coll Cardiol 2011;58:988–9.
    Crossref | PubMed
  82. Seicean S, Seicean A, Plana JC, et al. Effect of statin therapy on the risk for incident heart failure in patients with breast cancer receiving anthracycline chemotherapy: an observational clinical cohort study. J Am Coll Cardiol 2012;60:2384–90.
    Crossref | PubMed
  83. Seicean S, Seicean A, Alan N, et al. Cardioprotective effect of beta-adrenoceptor blockade in patients with breast cancer undergoing chemotherapy: follow-up study of heart failure. Circ Heart Fail 2013;6:420–6.
    Crossref | PubMed
  84. Pituskin E, Mackey JR, Koshman S, et al. Multidisciplinary Approach to Novel Therapies in Cardio-Oncology Research (MANTICORE 101-Breast): a randomized trial for the prevention of trastuzumab-associated cardiotoxicity. J Clin Oncol 2016:JCO2016687830. PMID: .
    PubMed